SU1051092A1 - Process for preparing thioquinolidines - Google Patents

Abstract

METHOD OF OBTAINING TIOCHINDOLINS General, formulas where RH, 2-CH, 2-OCH, O tchlychayuschie and the fact that, in order to increase the yield of the target product, simplify the process and expand the range of thiochindolines, aromatic amine hydrochlorides of the general formula KNg Hdl g where, is 4-CH5, 4 is OCHi,; and is reacted with 3-chlorobene (c) tyofen-2-aldehyde in the medium of an organic solvent at 78-90 s. O ate about co

Description

The invention relates to a new process for the preparation of thiochindolines of the general formula.

J

where, 2-CH, 2-OCH, which are similar in structure to some compound with antitumor activity, and can be used in medicine and in organic synthesis

The known method l is the preparation of unsubstituted thiochindoline () by a catalytic reaction between 2phenylquinoline and hydrogen sulphide at a high temperature.

The harsh conditions of the reaction (630 ° C, its low yield of 18%) make this method practically unacceptable under normal laboratory conditions.

A known method for the preparation of unsubstituted thiochindoline () from 3-nitrobenzo-c (a) thiophene, with intermediate production of 3-aminobenzo (c) thiophene and 1,2,3,4 tetrahydrobenzothieno C 3,2b) quinoline 2, in succession.

The method is multi-stage, labor intensive, low you-i

the moves of the final and intermediate products. Thus, 1,. 2, 3, 4-tetrahydrobenzothieno (3.2 V) quinoline is obtained in 4% yield.

A known method for the preparation of alkyl substituted thiochindolines based on 3-arylaminobene, zo (c) thiophenes .. When acylating (formylating) these compounds followed by heterocyclization, get 11-methylthiohindo-LIN (10% yield), 11-ethylthiohindoline (15% yield) and - 2, 3-dimethylthiochindoline (9% yield) L3j.

Significant disadvantages of this method are the increased sensitivity of the starting compounds to heating and Lewis acids and, as a result, low yields of the target products.

A known method for the preparation of unsubstituted (P, H) 4 and methyl-substituted (R 2-CH) j 3 thiochindolines by the Pfitzinger reaction by reacting 3-hydroxybenzo (c) thiophene and the corresponding isatin, followed by thermal decarboxylation of the formed tsonchoninic acid, 4 final product not specified. In this work, 3-methylthiochindoline-11-carboxylic acid is obtained in a yield of 25%. The yield of the final product is not specified. The reaction scheme is as follows:

tolir

i and

5th

doon

II Mr., Mr.-CH3

V-nG2-s1Nz

The disadvantages of the method are the low yield of the target product, the need to pre-obtain hard-to-reach isatins, the inability to obtain 2-methoxythiochindoline due to the unavailability of 5-methoxyisatin,

The purpose of the invention is to increase the yield of the target product, simplifying the process and expanding the range of thiochindolines.

The goal is achieved by the fact that according to the method for producing 45 thiochindolines of general formula I, ..

50

where, 4-CH, 4-OCH O is reacted with 3-chlorobenzo (c) thiophene-2-aldehyde;

NHrHdl

1 2-dH5,

in the environment of an organic solvent at 78-900C.

The yields of thiochindolines are,%, with (A); 42 (c); at 51 (B); R 2-OCH 84 (B);

The structure of the obtained thiochindolins was proved by the method of counter synthesis (using the example of unsubstituted thiochindoline), as well as by a combination of physicochemical methods (PMR, IR spectroscopy, the method of dipole moments).

Example 1. Preparation of 3hlbrbenzo (c) thiophene-2-aldehyde.

To 16.5 g (10.1 ml) of POCz, 8.5 g (8.9 ml) of DMF were added with stirring (0-2c) and stirring. The mixture is kept at this temperature for 20 minutes, and then a solution of 15 g (0.1 M) of 3-hydroxybenzo (c) thiophene in 20 ml of DMF is gradually added. After 30 minutes, the mixture is gradually heated to .80 ° C and kept for 3 hours at the same temperature. Then it is cooled, a thick resinous mass is poured onto ice and neutralized with solid soda to pH 7. The precipitate formed is filtered off, drained and transferred to a flask for distillation with steam. .

After distillation with steam and drying in a vacuum desiccator, 18.6 g (95%) of 3-chloro-benzo (in) thiophene-2-aldehyde with m.p. 109-110 ° C. The main physico-chemical characteristics of the preparation obtained (IR, PMR, mp) and the sample obtained according to method 5 are completely analogous.

Example 2. Getting thiochindoline (A,).

1 g of 3-chlorobenzo (c) thiophene-2-adhyde and 2.6 g of aniline hydrochloride are dissolved with weak heating in 25 ml of ethanle and the resulting solution is heated under reflux for 1 hour, cooled first to room temperature, then in a refrigerator () during the day. 0.5 g of hydrochloride hydrochloride in the form of yellow or yellow-red needles are obtained by filtration. Further cooling of the mother liquor gives an additional g of the substance. The total yield is 0.75 g.

Tyohindoline hydrochloride is dissolved by heating in a 10 ml helix and to the resulting bright yellow solution, 3 ml of a 10% NaCl solution is added with stirring. Complete bleaching of the solution is observed, which is then diluted with 3 times the amount of water. The colorless precipitate is filtered off, washed with water and dried in a vacuum desiccator. Receive 0.65 g of tyohindoline (55%) with so pl. 172p.

Found,%: C 76.34; H 3.61; N 5.75; S 13.28.

. , NS.

Calculated,%: C 76.57; H 3.66; N 5.95; S 13.62,

IR spectrum (liquid paraffin), cm: 1600 (cf.), 1560 (el.). Valence vibrations of the double bonds of a heteroaromatic ring:

910 (ae.) - nonplanar deformation vibrations of an isolated aryl hydrogen atom; 770 (p.), 735 (p.) - nonplanar deformation vibrations of four adjacent aryl hydrogen atoms.

PMR spectrum (solvent C1 C1), MD: 8.85-8.60 (m.H-6); 8.50 (s.N-I) 8.40-8.15 (m.N-4); 8.00-7.10 (m.H-1, 2,3,7,8,9).

Dipole moment (benzene, 25 С) 1, ЗД. Calculated by additive scheme

1.4D.

For the synthesized compound and for the known cyohindoline obtained by the counter synthesis of Q3j, all the indicated physicochemical characteristics completely coincide, which is evidence of the identity of these compounds. Example 3. Getting tyohindolina (B,).

1 g of 3-chlorobenzo (c) thiophene-2-aldehyde and 2.6 g of aniline hydrochloride are dissolved with weak heating (35–40 ° C) in 35 ml of DMSO, the resulting solution is heated in a water bath (85–90 s) in for 1 h. The flask with the solution is closed and placed at room temperature. (25 ° C) for 3 days. After the indicated period of time, otfil5 is filled with 0.4 g of tyohindoline hydrochloride, the mother liquor is kept at 17-18 ° C for 1 day. Additionally, 0.2 g of the substance is obtained. The total yield is 0.6 g. The resulting chloro-11-ditrate tyohindoline is transferred to the base, as described above. Receive 0.5 g of tyohindolina (42%), completely similar to the preparation obtained in example 2.

Example 4. Preparation of 2-methoxythioindindine (B, R 2-OCH).

2.73 g of 3-chlorobenzo (c) thiophene-2-aldehyde, 9.1 g of C-anisidine hydrochloride and 95 ml of DMSO are reacted as described above. 3.21 g (84%) of 2-methoxythiochindoline are obtained, m.p. .

Found,%: C 72.69; H 4.30; N 5.00; S 11.81.

, N05

Calculated,%: C, 72.43; And 4.18; N 5.28; S 12,08.

IR spectrum (liquid paraffin), cm: 1625 (cf.). Valence vibrations of double bonds of a heteroaromatic ring: 1025 (p.) - symmetric valence vibrations of the C-o fragment 905 (cf.) - nonplanar deformation vibrations of isolated aryl hydrogen atoms; 825 (p.) - non-flat deformation vibrations of two adjacent aryl hydrogen atoms, 760 (p.), 740 (p.) PMR spectrum - (CCI), MD: 8.83 8, 50. (M. H-6); 8.35 (s, H-11); 8.258, 00 (m.H-4); 7.85-6.95 (m.H-1.3, 7.8.9); 3.85 (s. C% O-group). Dipole moment benzene, 25s) 2, 1Д. Calculated by additive schemes 2, OD. Example 5. Obtaining 2-methylthiochindoline (B, R 2-CH5). 3 g of 3.-chlorobenzo (c) thiophene-2-aldehyde, 8 g of P-toluidine hydrochloride are added to 125 ml of DMSO in the reaction as described above. 1.92 g are obtained (51% of 2-methylthiochindoline, mp 162 ° C (lit. t. PL 160 ° C) 3). Found: C 76.8 V, H 4.20 N 5.77; .S 12.46. C, bN, NS., Calculated: C 77.08; H 4.45; N 5.62; S 12.86. IR spectrum (liquid paraffin), cm-H 1600 (cf. .). 1560 (el.). Valence vibrations of double p1x bonds of a heteroaromatic ring; 890 (cf.), 880 (cf.) - non-flat; Deformation vibrations of isolated aryl hydrogen atoms; 825 (p.) - non-flat deformation vibrations of two adjacent aryl hydrogen atoms; 760 (p.), 745 (p.) - non-flat deformation vibrations of four adjacent aryl hydrogen atoms. PMR spectrum (SCC), MD: 8.958, 68 (m.N-6); 8.48 (s.N-11); 8.388, 08 (m.N-4); 7.98-7.38 (m.N-1.3, 7.8 , 9); 2.55 (smetyl). The dipole moment (benzene) - 1.4 D. Calculated by the additive scheme. 1.5 D. Thus, the proposed method of producing thiochindolines compared to prototype 3, taken as the base object, provides higher yields of the target products (42-84%), expands their range, simplifies the process, allows the use of more accessible source components.

Claims (2)

METHOD FOR PRODUCING THIOCHINDOLINES of the general formula where R-H, 2-CH,, 2-OCH ", characterized in that, with the aim of increasing the yield of the target product, simplifying the process and expanding the range of thioindolines, aromatic amine hydrochlorides of the general formula · Hdl where R = H, · 4-СН ,, 4 - OCH ,, is reacted with 3-chlorobeneo (c) thiophene-2-aldehyde in the β-environment of an organic solvent at 78-90 ° C.